The present invention relates to a process for the preparation of chiral xcex2-amino acids and esters of the formula 
wherein X and Y are the same or different halo group, R2 is H or lower alkyl; which process comprises reacting a 3,5-dihalosalicylaldehyde of the formula 
with MEMCI or BnBr (Bn=benzyl) to obtain a protected 3,5-dihalosalicylaldehyde of the formula 
wherein P is Bn or MEM; treating the protected 3,5-dihalosalicylaldehyde with (R) or (S) phenylglycinol in tetrahydrofuran (THF) or toluene to produce an iminoalcohol of the formula 
reacting said imino alcohol with BrZnCH2CO2-t-Bu in N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO) or THF to produce an amino alcohol of the formula 
reacting the amino alcohol with lead tetracetate (Pb(OAc)4) to form an imine of the formula 
transesterifying, deprotecting, and hydrolyzing said imine in a one pot process to isolate a product of the formula 
The reaction provides for the preparation of (R) or (S) isomers with enantiomeric excess (ee) greater than 99%.
U.S. Ser. No. 08/890,907 discloses the following process for preparing xcex2-amino acid esters. 
Briefly in Scheme A, the chiral imine 1 derived from 3,5-dichlorobenzaldehyde and (S)-phenylglycinol is reacted with 2 equivalents of the Reformatsky reagent (BrZnCH2CO2tBu.THF) in NMP at xe2x88x9210xc2x0 C. to afford the corresponding amino alcohol product 2 as one enantiomer (ee greater than 96%). The amino alcohol 2 was then oxidatively cleaved with sodium periodate in ethanol in the presence of methyl amine to afford the corresponding phenyl imine 3. The xcex2-amino ester 4 was then isolated as a PTSA salt from THF and heptane with an overall yield of 63%.
The chiral xcex2-amino acids and esters produced by the process of the present invention are useful in preparing pharmaceutical agents known as xcex1vxcex23 integrin antagonists disclosed in W097/08174. It is therefore desirable to provide a process for the preparation of said amino acids and esters which is amenable to scale-up, and which employs raw materials which are readily available, resulting in high yield and a high level of optical purity which doesn""t require any chromatography and/or separation of diastereoisomers.
The present invention relates to a process for the preparation of chiral xcex2-amino acids and esters of the formula 
wherein X and Y are the same or different halo group, R1 is H or methoxyethoxymethyl (MEM) and R2 is H or lower alkyl; which process comprises reacting a 3,5-dihalosalicylaldehyde of the formula 
with MEMCI or BnBr (Bn=benzyl) to obtain a protected 3,5-dihalosalicylaldehyde of the formula 
wherein P is Bn or MEM; treating the protected 3,5-dihalosalicylaldehyde with (R) or (S) phenylglycinol in tetrahydrofuran (THF) or toluene to produce an iminoalcohol of the formula 
reacting said imino alcohol with BrZnCH2CO2-t-Bu in N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO) or THF to produce an amino alcohol of the formula 
reacting the amino alcohol with lead tetracetate (Pb(OAc)4) to form an imine of the formula 
transesterifying, deprotecting, and hydrolyzing said imine in a one pot process to isolate a product of the formula 
The reaction provides for the preparation of (R) or (S) isomers with enantiomeric excess (ee) greater than 99%.
The invention herein is directed to the preparation of xcex2-amino acids and esters of the formula 
and acid addition salts thereof wherein R2 is H or lower alkyl and X and Y are the same or different halo groups.
Synthetic schemes for the most preferred synthetic methods are outlined in Schemes I-IV and the following descriptions thereof. 
In Scheme I, 3,5-dihalosalicylaldehyde (A, X, Y=Cl, Br, I) was protected as a MEM derivative (B, P=MEM, X, Y=Cl, Br, I) or benzyl derivative (B, P=Bn, X, Y=Cl) by reaction, respectively, with MEMCI or benzyl bromine and potassium carbonate in DMF. The chiral imine C was formed from B and (S)-phenyl glycinol in THF in the presence of magnesium sulfate. C was reacted with two equivalents of Reformatsky reagent (BrZnCH2CO2tBu.THF) to stereoselectively form D (P=MEM, Bn, X, Y=Cl, Br, I). The amino alcohol residue of D (P=MEM, X, Y=Cl, Br, I) was oxidatively cleaved using lead acetate in methanol to form the imines E (P=MEM, X, Y=Cl, Br, I). Alternatively the oxidative cleavage can be performed with periodic acid in ethanol in the presence of methyl amine. The xcex2-amino esters were then prepared refluxing E (P=MEM, X, Y=Cl, Br, I) in the presence of excess of p-toluenesulfonic acid in ethanol followed by precipitation in THF/heptane. F (X, Y=Cl, Br, I) was obtained with good overall yield and high optical purity and chemical purity. Intermediates C, D, E are not isolated and are used subsequently as prepared without purification. 
In Scheme II, the chiral imines 6a (P=MEM) and 6b (P=Bn), were prepared by reaction of the corresponding protected 3,5-dichlorosalicylaldehyde 5a (P=MEM), 5b (P=Bn) with (S)-phenyl glycinol in THF in the presence of magnesium sulfate followed by filtration and distillation of the solvent. Imine 6a was reacted with 2 equivalents of Reformatsky reagent (BrZnCH2CO2tBu.THF) in NMP for 1 hour at xe2x88x9210xc2x0 C. followed by quench with HCl/NH4Cl, extraction with MTBE and distillation of the solvents to obtain a crude product (100%) containing 7a as one diastereoisomer as determined by 1H NMR and TLC. The same reaction performed in DMSO at 20xc2x0 C. led to lower selectivity as 7a is isolated as a 95/5 mixture of diastereoisomer with 86% yield after chromatography. Reaction of imine 6b (P=Bn) in NMP was slower and was completed after 15 hours at xe2x88x925xc2x0 C. Compound 7b was isolated as one diastereoisomer as determined by 1H NMR and TLC. 
In Scheme III, the amino alcohol residue of 7a was oxidatively cleaved using lead tetra acetate in methanol to form the imine 8. 8 is refluxed in the presence of excess of p-toluenesulfonic acid in ethanol followed by precipitation in THF/heptane. The xcex2-amino ester 9 was obtained with 49% overall yield and ee greater than 99% as determined by chiral LC. Alternatively, the oxidative cleavage was performed with sodium periodate in ethanol in the presence of methyl amine or periodic acid in ethanol in the presence of methyl amine. 
In Scheme IV, the chiral imine 11 was prepared by reaction of the corresponding protected 3-bromo-5-chlorosalicylaldehyde 10 with (S)-phenyl glycinol in THF in the presence of magnesium sulfate followed by filtration and distillation of the solvent. Imine 11 was reacted with 2 equivalents of Reformatsky reagent in NMP at xe2x88x9210xc2x0 C. followed by quench with HCl/NH4Cl, extraction with MTBE and distillation of the solvents to obtain a crude product (100%) containing 12 as one diastereoisomer (as determined 1H NMR). The amino alcohol residue of 12 was oxidatively cleaved using lead acetate in methanol to form the imine 13. 13 was refluxed in the presence of excess of p-toluenesulfonic acid in ethanol followed by precipitation in TF/heptane. The xcex2-amino ester 14 was obtained with 45% overall yield (from unprotected salicylaldehyde) and ee greater than 99% as determined by chiral LC. 
In Scheme V, the chiral imine 16 was prepared by reaction of the corresponding protected 3-chloro-5-bromo salicylaldehyde 15 with (S)-phenyl glycinol in THF in the presence of magnesium sulfate followed by filtration and distillation of the solvent. Imine 16 was reacted with 2 equivalents of Reformatsky reagent in NMP at xe2x88x9210xc2x0 C., followed by quench with HCl/NH4Cl, extraction with MTBE, and distillation of the solvents to obtain a crude product (100%) containing 17 as one diastereoisomer as determined by 1H NMR. The amino alcohol residue of 17 was oxidatively cleaved using lead acetate in methanol to form the imine 18. 18 was refluxed in the presence of excess of p-toluenesulfonic acid in ethanol followed by precipitation in THF/heptane. The xcex2-amino ester 19 was obtained with 33% overall yield (from unprotected salicylaldehyde) and ee greater than 99% as determined by chiral LC.
Unless otherwise noted the starting materials for the process of this invention are all commercially available or can be prepared according to conventional methods known to those with skill in the art. All equipment employed is commercially available.
The following is a list of definitions and abbreviations used herein:
The terms xe2x80x9calkylxe2x80x9d or xe2x80x9clower alkylxe2x80x9d refer to straight chain or branched chain hydrocarbon radicals having from about 1 to about 6 carbon atoms. Examples of such alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl and the like.
The term xe2x80x9cL-phenylglycinolxe2x80x9d refers to a radical of the formula 
and is used interchangeably with the term (S)-phenylglycinol.
The term xe2x80x9cD-phenylglycinolxe2x80x9d refers to a radical of the formula 
and is used interchangeably with the term (R)-phenylglycinol.
The term xe2x80x9chaloxe2x80x9d as used herein refers to a bromo, chloro or iodo radical.
ee means enantiomeric excess
Bn refers to a benzyl radical
MEM refers to a methoxyethoxymethyl radical
THF refers to tetrahydrofuran
NMP refers to N-methylpyrrolidinone
DMSO refers to dimethylsulfoxide
NalO4 refers to sodium periodate
NH4Cl refers to ammonium chloride
CH3NH2 refers to methylamine
EtOH refers to ethanol
Pb(OAc)4 refers to lead tetraacetate
PTSA refers to para-toluenesulfonic acid
MTBE refers to methyl tert-butyl ether
NaOEt refers to sodium ethoxide
EtOAc refers to ethyl acetate
MgSO4 refers to magnesium sulfate
GC refers to gas chromatography.
The present invention provides a safe, convenient and cost effective manufacturing process for the preparation of chiral xcex2-amino acids and esters which is amenable to scale-up. The process utilizes raw materials which are readily available and cost efficient. Its convenience is demonstrated in that the synthetic route does not require either a chromatography or chemical or enzymatic separation of diastereoisomers. Its cost effectiveness is demonstrated by the final products being produced in high yield and a high level of optical purity.
The following non-limiting examples describe and illustrate a method for carrying out the process of the present invention, as well as other aspects of the invention, and the results achieved thereby in further detail. Both an explanation of, and the actual procedures for, the various aspects of the present invention are described where appropriate. These examples are intended to be illustrative of the present invention, and not limiting thereof in either scope or spirit. Those of skill in the art will readily understand that known variations of the conditions and processes described in these examples can be used to perform the process of the present invention.